Tuberculosis remains a serious global infectious disease responsible for at least 2 million deaths per year. The incidence of multiple drug resistant tuberculosis arguably poses the most significant public health threat for the twenty first century. CPZEN-45 is a derivative of caprazamycin which has been identified by leaders in the tuberculosis treatment community as having great potential for disease therapy. There have been very few new drugs developed in the last 30 years and none have yet come to market. CPZEN-45 is poorly bioavailable by the conventional routes of administration. Previously, we have demonstrated the potential for several drugs to be active following aerosol administration to the lungs. Very low doses (tens of 5g/kg) delivered to the lungs of guinea pigs resulted in a significant reduction in the burden of bacteria. This approach would supplement the standard of care for drug combinations without increasing toxicity. Capreomycin has been delivered in higher doses (mg/kg) and is more potent than delivered by the IM route. This drug has the potential to supplement or replace (based on achieving systemic MIC levels) capreomycin IM in the current standard of care for MDR-TB. It is postulated that direct, topical delivery of the caprazamycin derivative (CPZEN-45) to the lungs of infected guinea pigs will result in sufficiently high local concentrations to quickly eradicate bacterial populations and potentially sterilize the lungs. The implications of demonstrating this effect may be to reduce the duration of chemotherapy necessary to achieve a cure in drug resistant tuberculosis by ADDING to the current therapy. Spray dried CPZEN formulations will be prepared in particle sizes suitable for aerosol delivery. (a) Pharmacokinetics and (b) pharmacodynamics of inhaled CPZEN will be assessed in the low dose infected guinea pig model. Understanding (a) the distribution (local and systemic) of drug following aerosol administration and (b) its effect on reducing the burden of bacteria in various organs representing local and systemic regions is a prerequisite for proposing a human application. PUBLIC HEALTH RELEVANCE: HIV-associated tuberculosis infections and emergence of MDR-TB highlight the need for new effective anti-TB drugs, alternative therapies, regimens and new formulations to increase efficacy and reduce toxicity of anti-mycobacterial agents. Caprazamycin derivative CPZEN-45, a novel anti-TB drug candidate, may be effective in eliminating infection when administered to the lungs as a respirable powder. Direct, topical delivery of CPZEN-45 to infected lungs will results in relatively high local drug concentrations, which can more quickly eradicate active bacterial populations, thus rapidly sterilizing the lungs and reducing the duration of chemotherapy necessary to achieve a durable cure in drug-resistant pulmonary tuberculosis. The advantage of delivering aerosols to the lungs include: more rapid sterilization of patients with active TB or MDR-TB;increased therapeutic options for managing patients with MDR-TB;prevention of the emergence of drug-resistance and;enhanced opportunities for the development of new anti-TB agents.